FI107731B - Process for the preparation of chlorosulfate and sulfamate derivatives of 2,3: 4,5-bis-O- (1-methylethylidene) -beta-D-fructopyranose and (1-methylcyclohexyl) methanol - Google Patents

Abstract

A process for producing chlorosulfate and sulfamate esters of 2,3:4,5-bis-O-(1-methylethylidene)- beta -D-fructopyranose and (1-methylcyclohexyl)methanol is disclosed. The process involves a two step procedure involving in the first step reacting of an alcohol with sulfuryl chloride in the presence of a tertiary or heterocyclic amine base in a solvent selected from the group consisting of toluene, t-butyl methyl ether or tetrahydrofuran , and in the second step reacting of the resulting intermediate with an amine in a solvent selected from the group consisting of toluene, t-butyl methyl ether, tetrahydrofuran and lower alkanol .

Description

107731

FIELD OF THE INVENTION This invention relates to a process for the preparation of 2,3-bis-O- (1-methylethylidene) -β-D-fructopyranose and (1-methylcyclohexyl) methanol, chlorosulfate and sulfamate derivatives. : Chlorosulfate and sulfamate esters of 4,5-bis-O- (1-methylethylidene) -BD-fructopyranose and (1-methylcyclohexyl) methanol. In particular, the process comprises a two-step process involving the reaction of an alcohol with sulfuryl chloride in the first step in the presence of a tertiary or heterocyclic amine base in a solvent selected from the group consisting of toluene, t-butyl methyl ether or tetrahydrofuran. with an amine in a solvent selected from the group consisting of toluene, t-butyl methyl ether, tetrahydrofuran and lower alkanol.

BACKGROUND OF THE INVENTION Sulphamates of Formula I:

Rs _ / ~ \, ch2oso2nhr1

\ T: - / Λ 2 I

V: 25 *: **: where X is 0 or CH 2 and R 1f R 2, R 3, R 4 and R 5 are as defined herein, are known compounds having • · · ♦ 1.: have been shown to exert their anticonvulsant activity and thus • They are useful in the treatment of conditions such as · · · epilepsy. These compounds are disclosed in U.S. Patent Nos. 4,582,916 and 4,513,006, which also disclose methods for the preparation of such compounds.

One of the i: reaction formulas disclosed in these earlier patents covers the reaction of an alcohol of formula RCH, OH: ***: 35 with the formula C1SO2NH2 or ClSO3NHR! chloroformulphate in the presence of a base such as potassium t-butylate or sodium hydride (NaH) at a temperature of about -25 ° C to 25 ° C and in a solvent such as toluene, tetrahydrofuran (THF) or dimethylformamide (DMF) wherein 5 R is a group of Formula II:

Rs "P ^" r; Rs 10 There are two major drawbacks to this process. Another drawback is that it requires a combination of NaH and DMF, which is not controllable exothermic and therefore potentially explosive. See J. Buckley 15 et al., Chemical 6 Engineer News, July 12, 1982, page 5; and G. DeWail, Chemical & Engineering News, September 13, 1982. Another drawback is the use of highly toxic and corrosive chlorosulfonyl isocyanate (CSI) for the manufacture of sulfamyl chloride (C1SO2NH2) 20, which is not commercially available, not only difficult to handle due to its toxicity and corrosion, but also because it is available from one commercial supplier only.

Another known process for the preparation of compounds of formula I disclosed in the above-mentioned U.S. Patent No. 4,513,006 involves the reaction of an alcohol of formula RCH2OH with a sulfuryl chloride of formula SO2Cl2 in the presence of a base such as triethylamine or pyridine at a temperature of about 30 ° C. from about -40 ° C to about 25 ° C in a diethyl ether or methylene chloride solvent to prepare the chlorosulfate '1' of the formula RCH 2 SO 2 Cl. The chlorosulfate of RCH 2 SO 2 Cl · · · · can then be reacted with the amine 35 of R 1 NH 2 at a temperature of about -40 ° C to-25 ° C in methylene chloride or acetonitrile solvent to prepare the compound of formula I. This process (using diethyl ether, methylene chloride, and acetonitrile solvents) yields, in relatively low yields, the final product of Formula I as compared to the process of this invention.

The final process disclosed in those two patents involves the reaction of the chlorosulfate of formula RCH 2 SO 2 Cl formed as described above with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile to give the azo sulfate of formula RCH 2 SO 2 N 3. The azide sulfate is then reduced to a compound of formula I wherein Rx is hydrogen by catalytic hydrogenation. The disadvantage of this method is that explosions can occur when handling azide compounds. The method further comprises converting a chemical that involves reducing the azide to an NH 2 group.

It is an object of the present invention to provide a new and improved process for the preparation of compounds of formula I using readily available materials which can be carried out under safe conditions and in relatively high yields. The advantages of the present invention have been partly described below, and some will be apparent from this description and by comparison with prior art methods described in the section below.

SUMMARY OF THE INVENTION According to the present invention, compounds of the formula ···: :: I are: 30A “, CH; OSOjNHR, ······························· · Where X is O or CH 2 and R 1f R 2, R 3, R 4 and R 5 are as defined below, is synthesized in two steps by reacting an alcohol of formula RCH 2 OH wherein R is a group of formula II: in a solvent selected from the group consisting of toluene, t-butyl methyl ether (TBME) or tetrahydrofuran (THF), preferably in toluene to form a compound of formula RCH 2 SO 2 Cl (formula III), and then in a second step, administering a compound of formula III with an amine of formula R 1 NH 3 in a solvent selected from THF, TBME, toluene and lower alkanol (e.g. methanol or ethanol), preferably in tetrahydrofuran, to give 20 formula I is: _ ^ \. Ch2oso2nhr1

R4 R3 I

• · · • · • «· 25

It is to be understood that the foregoing general and following detailed description is given by way of example only and is not intended to limit the invention as claimed.

Detailed Description of the Invention <tt #. Reference will now be made in detail to certain prior art embodiments of the invention. Examples of exemplary embodiments of the en- * · *. ** are described in the following section of the prefixes.

• «· • · • · # · · • · 107731 5

The novel process of the invention is inherently much safer than the known process employing a potentially explosive combination of NaH / DMF. It also uses sulfutyl chloride and ammonia instead of the highly toxic and corrosive chlorosulfonyl isocyanate (CSI). Further, sulfuryl chloride is more commercially available and much cheaper than CSI. In addition, the process yields relatively high yields of about 85-97% compared to known prior art processes in which the yields are in the range of about 1% to 60%. The obvious reason for the high yields is the particular choice of solvents selected for each step of the reaction sequence. The combination of inexpensive and readily available sulfuryl chloride and higher yields results in a much more economical and / or safer method compared to previously known methods.

More particularly, this invention relates to a process for the synthesis of compounds of Formula I: 20 µ / CHaOSOaNHR,

R 8 -> R / R 3 - wherein X is CH 2 or O; * R 25 R is hydrogen or C 1-6 alkyl; and R 2, R 3, R 4 and R 5 are independently hydrogen or alkyl - and when X is O, R 2 and R 3 and / or R 4 and R 5, together, may be a methylenedioxy group of formula IV Where R6 and R7 are the same or different and are 35 hydrogens, alkyl or both are alkyl and joined to 6,107,731 to form a cyclopentyl or cyclohexyl ring, provided that R 6 and R 7 cannot both be hydrogen at the same time.

In particular, Rx is hydrogen or alkyl having from about 5 to about 4 carbons such as methyl, ethyl and isopropyl. The alkyl groups R 2, R 3, R 4, R 5, R 6 and R 7 are 1-3 carbon and are methyl, ethyl, isopropyl and n-propyl. Throughout this specification, alkyls are straight-chain and branched alkyl groups.

This process is particularly useful for preparing compounds of formula I wherein X is oxygen and both R2 and R3 and R4 and R5 together are methylenedioxy groups of formula IV wherein R6 and R7 are each alkyl.

The process comprises reacting an alcohol of formula RCH 2 OH with a sulfuryl chloride of formula SO 2 Cl 2 in the presence of a tertiary or heterocyclic amine base such as pyridine, pyridine derivatives or triethylamine, preferably pyridine at a temperature of from about -78 ° C to about 40 ° C. such as toluene, t-butyl methyl ether (TBME) or tetrahydrofuran (THF), preferably toluene, to give the chloro

V 'phate, it is a compound of RCH 2 SO 2 Cl where R is of formula II

• · *, ·, * Group of 25:?! 'i I I • · · 30

The chlorosulfate of formula III RCH 2 SO 2 Cl is then reacted with the amine of formula I 1 at a temperature of about -50 ° C to about 50 ° C, more preferably about 15 ° C to about 20 ° C in a solvent such as THF, TBME,? # <<: 35 in toluene, methanol, or ethanol, preferably? 107731 in THF to give a compound of formula I.

The reaction with the amine of formula R 1 H 3 can be carried out using a suitable source of amine, primarily ammonia gas (R 2 = H), from an ammonia gas generating source such as aqueous or pressurized water at about 50 psi, preferably about 20-30 psi. of anhydrous ammonia, or the amine can be bubbled into the reaction. Reaction 10 can also be carried out using a pre-saturated solution of ammonia in THF.

To obtain a purer product, the compound of formula I can be recrystallized by conventional methods such as, for example, ethanol / water or ethyl acetate / hexane.

Starting materials of formula RCH 2 OH can be obtained commercially from Aldrich Chemical Corporation or synthesized by methods well known in the art. For example, starting materials of formula RCH2OH wherein R2, R3, R4 and R5 are methylenedioxy groups of formula IV can be obtained by R.F. Brady's method of "Carbohydrate Research", Vol. 15, pp. 35-40 (1970) or by reacting the trimethylsilyl enol ether of the R6COR7 ketone or aldehyde with fruc. with a dose of about 25 ° C in a solvent 25 such as an alkyl halide, e.g. methylene chloride, a protic acid such as hydrochloric acid or a Lewis acid such as. in the presence of zinc chloride. Trimethylsilylenoleate- • * · ♦. ·. ; terrier reactions are described by G.L. Larson et al., J. Org. Chem. Butter. 38, No. 22, p. 3935 (1973).

* A particularly preferred process of the present invention involves the reaction of a compound of formula V:? / -O. , .ch2oh ο ·· <:.:: CH3 ^ A3— (Jl ~ ch3 35 7 ^ 0 Vf v * · .. · ch3 ch3 «· • t 107731 8 with a sulfuryl chloride of formula S02C12 in the presence of an amine base such as pyridine in toluene at a temperature of about 0 ° C to about 40 ° C and at about atmospheric pressure to give a compound of formula VI: 5

r-O 0 .CH 2 SO 2 Cl

CH3 '^ X i \ jL-CH3

/ ^ ö 0- ^ y VI

ch3 ch3 10

The compound of formula VI is then reacted with ammonia at a pressure of about 30 psi in THF at a temperature of about 15-20 ° C to give a compound of formula VII: -O, CH 2 SO 2 NH 2

RCX

ch3 - ^ /; —t i ^ ch3 20 / "- ö Vf v" ch3 CH3

The same procedure may be used to prepare the L-fructopyranose derivative enantiomer in place of the D-fructopyranose enantiomer of formula VII using the L-enantiomer starting material instead of the D-enantiomer of formula V.

. The invention will now be illustrated by way of example. These examples are not to be construed as limiting the scope of this invention, but are intended to be understood by reference to the foregoing detailed and general description, to make the present invention more comprehensible, and to the method of preparation of the invention. «... · to put the method into practice.

• · * 1 · • · · · · · · 107731 9

examples

Examples 1 and 2 illustrate the preparation of intermediates of this invention. Examples 3 to 5 and 14 are examples of the preparation of final desired products by the two-step process of the invention, examples 6 to 13 of the comparative examples known in the art. Table 1 compares the yields of Examples 6-10 of the known methods with the yields of the two-step processes (Examples 3-5) of this invention in the preparation of the compound of Formula VII.

Table 2 compares the yields of the process (Example 14) of this invention with the yields of known methods (Examples 11-13) in the preparation of (1-methylcyclohexyl) methanesulfamate. As shown in Tables 1 and 2 of Table 15, the process of the present invention provides the final product in higher yields than known processes and the final product in excellent purity.

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107731 12

Example 1 Preparation of 2,3-4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose

Under nitrogen protection, acetone (144.0 liters, 113.0 kg, 5 1946 moles) was cooled to 0-10 ° C. Concentrated sulfuric acid (7.2 liters, 13.2 kg, 135.6 moles) was added with stirring (about 0.5 h) so that the temperature did not rise above 20 ° C (jacket temperature -15 ° C). External cooling was continued and D-fructose 10 (12.0 kg, 66.6 moles) was added stepwise (in 2.0 kg steps) over 2 hours while maintaining the temperature between 8-15 ° C. The suspension was stirred at room temperature for a further 2-3 hours after all fructose had dissolved. The solution was then cooled to 5 ° C and 50% sodium hydroxide (24.0 kg, 297.6 mol) was added at a rate such that the temperature of the solution was maintained below 20 ° C (the addition was complete for one hour). at -15 ° C). The resulting slurry was centrifuged to remove the precipitated salt (sodium sulfate). The solvent was removed from the filtrate by distillation in vacuo and the remaining oil was stored at room temperature. The semi-solid reaction product was dissolved in t-butyl methyl ether (48.8 kg, 66.4 liters). The solution was washed with distilled water (2 x 9.0 liters) and concentrated to give an oil. The oil was dissolved in a mixture of hexane (24 liters *: · * *) / isopropanol (3.5 liters) with gradual warming to ··· 60 ° C. The product crystallized upon cooling. The solid was collected by centrifugation and dried in a vacuum oven at 38 ° C for 8.0 hours to give 10.8 kg · · · 30 (yield 62.4%, purity 100%). By GLC), a white solid, m.p. 95-96 ° C.

• * · • · ·

• I

• · · t

• I

• * · • · · · · »· • · · • • • • • • 107731 13

Example 2 2,3: Preparation of 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranosyl sulfonyl chloride (chlorosulfate) A solution of sulfuryl chloride (486.9 g, δ 3.60 mol) and toluene 4.0 liters) was cooled to -10 ° C. To the cooled sulfuryl chloride solution was added a solution of the alcohol of Example 1 (782.4 g, 3.00 moles) and pyridine (285.3 g, 3.60 moles) in toluene (4.0 liters). The addition rate was adjusted to maintain the reaction temperature between -10 and 5 ° C (time required 1.5 hours). A white solid immediately precipitated from the reaction mixture. After the addition was complete, the cooling bath was removed and the mixture was stirred for 2.0 hours. The reaction mixture was diluted with distilled water (4.0 liters) and the resulting layers were separated. The organic layer was then washed successively with 10% citric acid solution (2.6 L), distilled water (2.6 L), saturated sodium bicarbonate solution (2.6 L), and saturated sodium chloride solution (2.6 L). Removal of the solvent by distillation of tis-20 in vacuo (bath at 45 ° C / < 5 mm) gave chlorosulfate (1101 g, 102.2%) as an almost colorless oil. The purity of the product was found to be 98.3% (w / w, based on GLC) with a harvested yield of 100.5%.

• · · *. · · Example 3 • · 25 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructo- *: **: Preparation of pyranose sulfamate (ammonium 30 · 1 · psi PREPARATION: To a 12.0 liter stainless steel autoclave was added chlorosulfate of Example 2 (1076.4 g, 3.0 molar · 30 L) in tetrahydrofuran (8.0 L). The autoclave was then pressurized with dry ammonia to 30 psi and agitated (400 rpm) at ambient temperature for 24.0 hrs · · ··· 1 h, mild exotherm was observed after 2.0 h ( From 25 ° C to 38 ° C) .The autoclave was depressurized by evacuating them to 35. The pale yellow solution containing a white granular solid was filtered and the filter cake washed tetrahydrofuran (400 mL) Tetra-hydrofuran was removed in vacuo (50 ° C, water vacuum) to give the product as a pale yellow oil 5 (1110.0 g, 109.0%). The oil was slurried in n-hexane (2.1 L) and heated on a water bath for 0.5 h. The oil turned to a white paste and then crystallized. After cooling to room temperature, the title compound was collected by filtration and air dried for 24.0 hours (955.1 g, 93.8% yield and 99.7% purity by GLC, yielding a corrected yield of 93.5%).

A sample (900 g) was recrystallized from 95% ethanol (900 mL) by the addition of distilled water (1800 mL) and the pH was adjusted to 8-8.5 by addition of 50% NaOH (3.5 mL). The solid was collected by filtration in vacuo and air drying (72.0 hours) to give the title compound (828.0 g, isolated yield 92.0%, purity 100.1% by GLC) as a white solid, m.p. 123-124 ° C.

Example 4 Preparation of 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate (ammonolysis with ammonia gas bubbles): 500 ml 4-neck round bottom flask, equipped with a hanging stirrer, bubbling *: ** device, thermometer, and inlet tube, 19.90 g (0.0556 mol) of the chlorosulfate of Example 2, * ··· dissolved in 200 of any tetrahydrofuran were placed. Dry ammonia was bubbled into the solution at room temperature for about 5 hours. The reaction mixture was filtered to remove the precipitate and the solvent removed in vacuo. The oil was slurried in hexane (50 mL) by heating in a water bath until it turned to a white paste. The oil crystallized under stirring while cooling to room temperature. The mixture was left: ***: 35 in place at room temperature overnight. The mixture was then filtered, washed with hexane, and air dried to give the title compound as a white solid (17.11 g, 96.2% purity by GLC, 87.2% yield).

Example 5 Preparation of 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate (saturation ammonium)

Dry ammonia was added to 490 kg THF until a pressure of 22 psi was reached. While maintaining a pressure of 10 to 22 psi, a solution of the chlorosulfate (303 kg, 845 mol) prepared in Example 2 dissolved in 415 kg of THF was pumped into a pre-saturated NH 3 / THF solution for 2 hours while maintaining an internal temperature of 15-20 ° C. After 3 hours, excess ammonia was removed and the reaction mixture was filtered. The THF solution was co-concentrated in vacuo to a syrup, diluted with isopropanol (185 kg), and concentrated again. The resulting residue was dissolved in a solution of isopropanol (150 kg) and white spirit (370 kg) containing 8.0 kg of activated charcoal and heated at 80 ° C for 30 minutes. The warm solution was filtered to remove charcoal and cooled. After cooling to 0-5 ° C, the title compound was collected by filtration and dried in vacuo at 45 ° C (239 kg, 83.3% yield).

Example 6 ♦ *: ** ί (Comparative Example) Preparation of 2,3: 4,5-bis-O- (1-methylethylene * j · dene) -BD-fructopyranose sulfamate: * A solution of the alcohol of Example 1 (15.0 g, 0.0576 mol) and pyridine (15 ml, 0.18 to 30 mol) in methylene chloride (60 ml) was cooled in a dry ice / isopropanol bath. To -40 ° C. A solution of sulfuryl chloride (16.0 g, 0.118 mol) in methylene chloride (10 ml) was added gradually with stirring (about • *: · 50 minutes) so that the temperature did not rise above : 35 -25 ° C. The ice bath was removed immediately after the addition was complete and the reaction mixture was stirred for an additional 2 hours. During this time, the pale yellow precipitate turned to a lumpy brown solid. The solvent was removed in vacuo to give an sticky brown residue. The residue was dissolved in 100 ml of methylene chloride and dry ammonia was bubbled through the mixture overnight at ambient temperature. The dark reaction mixture was concentrated in vacuo to give 47.7 g of the title compound as a black residue. The purity of the crude product was found to be 15.10% based on GLC 10, thus yielding 36.83%.

Example 7 (Comparative Example) Preparation of 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate

The reaction was carried out in the same manner as in Example 15 cat 6 except that acetonitrile was used in place of methylene chloride. The title compound was isolated as a black residue (45.77 g). The purity of the crude product was found to be 25.8% with GLC corrected yield thus being 60.40%.

Example 8 (Comparative Example) Preparation of 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate

The reaction was carried out in the same manner as Example ·· * .1 · in cat 6 except that in the first step methylene chloride · · V .; Instead of 25 rids, ether was used. The title compound was isolated as a black residue (42.84 g). The purity of the crude product was found to be 14.8% by GLC with a corrected yield of 32.43%.

* ·

Example 9 · · · 30 (Comparative Example) Preparation of 2,3: 4,5-bis-O- (1-methylethyl-lidene) -BD-fructopyranose sulfamate ····· · · ... The reaction was carried out in the same manner as in Example - • · ··· 1 cat 6 except that as solvent 1 (methylene chloride) j: '; ether was used instead of 2 and acetonitrile was used as a solvent instead of 2: methylene · 1: 35 chloride (see table «31 10 107731 17 pt. 1). Further work-up gave a black residue (43.82 g). The purity of the crude product was 18.70% with GLC corrected yield thus 41.91%. Example 10 5 (Comparative Example) Preparation of 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfamate

The reaction was carried out in the same manner as in Example 8 except that the chlorosulfate / methylene chloride solution was placed in a pear-shaped flask and cooled in a 10 mL ice / isopropanol bath. Dry ammonia was bubbled through the mixture for about 30 minutes; the flask was then sealed and allowed to slowly warm to room temperature overnight. The flask was cooled back before opening and the mixture was concentrated in vacuo to give the title compound as a brown tar. The crude product was found to be only 0.55% pure by GLC, yielding a corrected yield of 1.08%.

Example 11 Preparation of (1-methylcyclohexyl) methanesulfamate (Comparative Example)

A solution of (1-methylcyclohexyl) methanol (7.4 g, 0.057 mol) and pyridine * · * '(15 mL, 0.179 mol) in methylene chloride (100 mL) was cooled under nitrogen. was cooled to -10 ° C in an ice / methanol bath. With stirring ** '*, a solution of sulfuryl chloride (16.0 g, 0.118 mol) in methylene chloride (20 ml) was added gradually (over 10 hours) without increasing the temperature. • · above -5 ° C. The ice bath was removed and the false yellow solution was allowed to warm slowly to room temperature over a period of 2.0 hours. The solvent was removed in vacuo ... and the resulting yellow slurry was slurried in acetonitrile (140 mL). Dry ammonia was bubbled through a mixture of · · · · · J for 4.0 h. The mixture was filtered, washed with fresh: **: 35 acetonitrile and concentrated in vacuo to give the title compound (7.12 g) as a dark oil The crude product was found to be only 2.24% pure by GLC, thus correcting for a yield of 1.34%. Comparative Example) Preparation of (1-methylcyclohexyl) methanesulfamate

The reaction was carried out in the same manner as in Example 11 except that diethyl ether was used in place of methylene chloride as solvent (see Table 2). The product was not isolated at all by GLC analysis. Example 13 (Comparative Example) Preparation of (1-methylcyclohexyl) methanesulfamate

The reaction was carried out in the same manner as Example 15 in Cat 11 except that methylene chloride was used in place of acetonitrile as solvent 2 (see Table 2). The product (9.85 g) was isolated as a dark oil. The purity of the crude product according to GLC was 29.1% with a corrected yield of 23.97%.

Example 14 Preparation of (1-methylcyclohexyl) methanesulfamate

The sulfuryl chloride (18.67 g, 0.138 mole) was cooled in toluene (150 mL) to -50 ° C under argon-protective ice / acetone bath. A solution of 1-methyl-1-cyclohexane methanol (14.74 g, 0.115 mol) and pyridine (10.94 g, 0.138 mol) in toluene (150 ml) was added gradually (about 40-50 minutes). Na) so that the temperature did not rise above 30 -45 ° C. The ice bath was removed immediately after the addition.

After stirring for a further 30 minutes, water (300 ml) was added and the layers were separated. The organic layer was washed with 10% citric acid (2 x 60 mL), water (2 x 100 mL), saturated sodium bicarbonate (1 x 100 mL), ϊ *: 35, and saturated sodium chloride (1 x). 200 ml), then dried over solid sodium sulfate, filtered and evaporated in vacuo to give chlorosulfate (23.53 g, 90.6% yield) as a tan oil. The oil was dissolved in tetrahydrofuran (300 ml) and the solution was placed in a 1.0 liter autoclave (fitted with a glass liner). The autoclave was pressurized with dry ammonia until 28 psi and stirred (290 rpm) at ambient temperature for 16 hours. After 1.0 hours, mild exotherm (22-35 ° C) was observed. From the autoclave the head-10 I applied pressure to the air. Serosex was filtered and the solvent removed in vacuo to give 20.41 g of the title compound as a yellow oil. The purity of the product by GLC was 95.0% with a corrected yield of 81.33%.

Comparison of the Examples (Examples 3-5 and 14) of this invention with the previously known Comparative Examples (Examples 6-13) in Tables 1 and 2 demonstrates the advantages of using the particular selected solvents in the process of the present invention, which produce surprisingly better results over previously known methods. . Direct comparison of Example 4 of the invention using primary solvents of the invention, for example toluene and THF, with reference to Comparative Examples 6-9

IM

*. * * 1 shows an improvement in yield of at least 40% and a significant increase in the yield of the final product 2,3: 4,5-bis-O- (1-methylethylidene) -BD-fructopyrra * ϊ ** ose. purity healing. Analytical ··· improvements in the method result are shown in Table 2

MM

For the preparation of (1-methylcyclohexyl) methanesulfamate.

The scope of the present invention is not limited to the description, examples, signs and proposed embodiments described herein and may be modified without departing from the spirit of the invention. For example, other sulfamates may be prepared using the method of the invention other than: ***; 35 for the preparation of the compounds exemplified herein.

• m »

• I

The process applications and methods of the present invention can be carried out by any synthetic method and technique known or appreciated by those skilled in the chemical and pharmaceutical process fields at this time. Thus, it is an object of this invention to include any modifications and variations of this invention provided that they are within the scope of the appended claims and their equivalents.

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Claims (17)

107731 A two-step process for the synthesis of sulfamates of the formula I: 5 - (-) - CH 2 OSOsNHR, R 8> -Λ, R / Ra. Wherein X is CH 2 or oxygen; R 1 is hydrogen or alkyl; and R 2, R 3, R 4 and R 5 are independently hydrogen or alkyl and when X is oxygen, each of R 2 and R 3 or R 4 and R 5 together may be a methylenedioxy group of formula (IV): Wherein R6 and R7 are the same or different and are hydrogen, alkyl, or alkyl joined together to form a cyclic ring. a lopentyl or cyclohexyl ring, provided that • R5 and R7 cannot both be H at the same time, characterized in that in the first step there are 25 ColioliOH of the formula RCH2OH wherein R is a group of the formula • · • · · *: va II is:!: R; r, .1 ··. 30 ^ • · · · · · · · ;; / react with sulfuryl chloride in tertiary or in the presence of a heterocyclic amine base in a solvent selected from the group consisting of toluene, t-butyl methyl ether or tetrahydrofuran, 107731 to form a compound of formula III: RCH 2 SO 2 Cl 5 and, in a second step, a compound of formula III reacting the compound of formula I with an amine of formula R 1 H 3 in a solvent selected from the group consisting of toluene, t-butyl methyl ether, tetrahydrofuran and Alem-alkanol to form the sulfamate 10 of formula I. Process according to Claim 1, characterized in that in the first step the reaction between the compound of formula RCH 2 OH and the sulfuryl chloride is carried out in toluene. 15 3. Process according to Claim 1, characterized in that, in a second step, the reaction of a compound of formula III with an amine of formula R 1 -NEL 1 is carried out in tetrahydrofuran. Method according to one of Claims 1 to 3, characterized in that in the first step. the tertiary or heterocyclic amine base is a py • • ·. a ridine, a pyridine derivative or a triethylamine. * · · *. Process according to Claim 4, characterized in that the amine base is pyridine. • · · ···! 25 6th The honey according to any one of claims 1 to 5. *: A process characterized in that in the first step the reaction of the compound of formula RCH20H with sulfuryl chloride is carried out at a temperature of -78 to 40 ° C, preferably; -10 to 5 ° C. . The process according to any one of claims 1 to 6, characterized in that, in the second step, the reaction of a compound of formula III with an amine of formula R, NH 2 ··· • # '... · is carried out at -50 to 50 ° C, preferably 15 to 20 ° C. • · 107731 Process according to one of Claims 1 to 7, characterized in that it further comprises a step of recrystallization of the compound of formula I. A process according to claim 8, characterized in that the recrystallization step is carried out using a recrystallization medium selected from alcohol and water or from an ethyl acetate / hexane mixture. Process according to one of Claims 1 to 9, characterized in that, in a second step, the reaction of the compound of the formula III with an amine of the formula is carried out at a pressure of 101.33 to 344.74 kPa, preferably 206.84 to 151.68 kPa. Process according to one of Claims 1 to 9, characterized in that, in a second step, the reaction of a compound of formula III with an amine of formula RiNH5 is carried out in a pre-impregnated amine solution. The process according to any one of claims 1 to 9, characterized in that in a second step ... the reaction of a compound of formula III with an amine of formula R., NH 2 is carried out by bubbling the amine with a solution. A compound of formula III. Process according to any one of claims 10 to 12, characterized in that the amine of the formula R 1 NH 2 is ammonia. • · · ϊ: I Process according to claim 11, characterized in that the amine of the formula R1NH2 is NH4OH. . ···, 30 A process according to any one of claims 1 to 14, characterized in that said sulfate is 2,3: 4,5-bis-O- (1-methylethylidene) -β-Df-ructo- · · · 5 ... · pyranose sulfamate; 2,3: 4,5-bis-O- (1-methylethylidene) -...: β-L-fructopyranose sulfamate or (1-methylcyclohexyl) methane sulfamate. • · 107731 Process according to any one of claims 1 to 14, characterized in that said compound of formula III is 2,3: 4,5-bis-O- (1-methylethylidene) -β-D-fructopyranose sulfonyl chloride or 2,3: 4 , 5-bis-O- (1-methylethylidene) -β-L-fructopyranose sulfonyl chloride. 17. A two-step process for the synthesis of sulfamates of Formula VII: - In the first step, the compound of Formula V is: -o, ch 2 O 20 0 "" ( Is reacted with sulfuryl chloride in a toluene solvent in the presence of pyridine at a temperature of about -10 ° to -5 ° C to give a compound of formula VI is • «3. r-o xch2oso2ci: 3 J-ch3 ch3 ch3 ♦ ♦ ·: ··: 35 107731 and then in a second step, the compound of formula VI is reacted with gaseous ammonia at about 96.53 to 206.84 kPa pressure in tetrahydrofuran at a temperature of 15 to 20 ° C to prepare 5 of the compound of formula VII and then recrystallizing the compound of formula VII from an ethanol-water solvent. * 1 • • • • • • • • • • • • • • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · * · • · · * · • «107731